Many carcinogenic compounds occurring in the environment require metabolic activation before they will interact with cellular constituents and initiate tumor formation. For polycyclic hydrocarbons and carcinogenic amines, the activation reaction is an oxidation catalyzed by cytochrome P-450. It is proposed to study how these reactions are modified by drugs and environmental contaminants in the organs where exposure is likely, liver, lung and small intestine. The modifiers of the oxidation reaction scheduled for study are those compounds known to form inhibitory complexes with cytochrome P-450 during their metabolism, e.g., amphetamines, SKF 525-A and piperonyl butoxide. Also, the inductive effects of these compounds on procarcinogen activation will be studied. The formation of inhibitory cytochrome P-450 metabolic intermediate (MI) complexes and their effects on the oxidation reactions will be investigated in isolated perfused organs (liver, lung) in isolated cells (liver) in microsomal fractions and reconstituted purified enzyme systems. Analysis of metabolism, both for MI complex formation and procarcinogen activation (benzopyrene, 4-aminobiphenyl), will use high pressure liquid chromatography to obtain metabolic profiles, overcoming the limitations of present methodology. The project will result in the elucidation of the nature of the intermediate or reaction responsible for MI complex formation, and an understanding of how this affects procarcinogen activation and, hence, the incidence of cancer in the organism.